Multiple sclerosis (MS) is caused by an uncontrolled immune response against self-antigens in the central nervous system. The autoreactive components in the immune system are usually controlled by regulatory T cells (T{reg}). Not surprisingly, deficits in the T{reg} compartment are associated to MS and the susceptibility of mice to develop experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Thus, the study of the molecular mechanisms controlling T{reg} differentiation is needed to understand MS pathology and identify new therapeutic targets;these studies, however, cannot be easily performed in mammals. Worms and flies have been useful in the identification of the mechanisms governing innate immunity, but invertebrates do not have T{reg}. We found that the zebrafish has an immune system that shares several features with its mammalian counterpart, including the genes driving T{reg} differentiation. In this application we will use mice and zebrafish to identify the molecular pathways that control T{reg} generation. This goal will be achieved by three independent approaches: 1. Bioinformatic identification of transcription factors controlling T{reg} differentiation. 2. High throughput screen to identify chemicals that regulate T{reg} differentiation. 3. Characterization of the role of the transcription factors and chemical compounds on T{reg} activity during the course of EAE. This project has the potential to identify therapeutic targets for the management of MS, and to establish the zebrafish as a platform for the high throughput identification of immunomodulatory drugs. In summary, this is an innovative project that will combine the experimental advantages offered by mice and zebrafish to identify pathways controlling T{reg} generation and is consistent with the aims of the New Pathway to Independence Award Program.